7. Project Summary Abstract The group of progressive optic neuropathies referred to as ?glaucoma? is the leading cause of irreversible blindness worldwide and one of the primary causes of blindness in the United States. Three challenges in managing glaucoma today are: that approximately half of people with glaucomatous visual field loss have not been diagnosed, that measures of optic nerve rim area or retinal nerve fiber layer (RNFL) thickness cannot distinguish between axons of healthy and dysfunctional ganglion cells, and that it is difficult to distinguish patients with rapidly progressing glaucoma from those with relatively stable glaucoma. This research project proposes to address these challenges by determining whether properties of individual retinal nerve fiber bundles (RNFBs) can provide rapid objective detection of eyes with glaucomatous visual field damage, determining which properties best discriminate stable versus progressing damage, and employing psychophysical tools that can differentiate between healthy and dysfunctional axons. The proposed research will use advanced adaptive optics (AO) retinal imaging systems to perform high-resolution analysis of the properties of individual RNFBs in well-characterized patients with glaucoma and age-similar controls. This has the potential to dramatically improve ability to detect early changes in RNFBs, and better differentiate moderate from advanced damage. Specific Aim 1 will assess width, thickness and reflectance of individual RNFBs, as well as bundle spacing, in and near regions of damaged RNFL in patients with glaucoma, and in undamaged RNFL in age-similar controls. This will determine which RNFB properties are best for detecting early damage and which are best for differentiating moderate from advanced damage. Specific Aim 2 will assess distributions of highly-reflective substructures within individual RNFBs; the density of these substructures is reduced in damaged RNFBs and may account for decreased RNFL reflectance seen with clinical devices. Specific Aim 3 will develop a high-throughput optical coherence tomography (OCT) system for imaging RNFBs and their substructures in 3 dimensions. Specific Aim 4 will test hypotheses about ganglion cell dysfunction, death or axonopathy, relating functional defects to alterations in properties of corresponding RNFBs. These aims will provide insight into the biology underlying reflectance defects seen with clinical devices, and new tools for use in clinical trials.